Vaccine administration via intact skin, also called transcutaneous immunization (TCI) is a new approach recently introduced as a possible vaccination method and has advantages over traditional vaccination. However, inefficiency of delivering antigens (especially particulate antigens) through the skin barrier is a major limitation in applying this approach to immunization in general. Both retinoic acid and oleic acid affect skin epidermal Langerhans cells (LCs) by decreasing LC density and changing LC morphology. Since both molecules contain long hydrophobic fatty acid chains, they might enhance the entry of particulate antigens containing lipid membranes such as inactivated viruses and virus-like particle antigens when introduced via skin immunization. In this study, I hypothesize that the use of skin penetration enhancers (retinoic acid and oleic acid) will improve the transdermal delivery of soluble and particulate antigens and thus will enhance the immune responses to the antigens after skin immunization. Influenza virus will be used as a model particulate antigen in this study since it is known to induce strong immune responses after systemic or mucosal immunization and easily available. The hypothesis will be tested by the following specific aims. Using a chromophore conjugated albumin and inactivated influenza virus, I will evaluate the effect of skin permeation enhancers (retinoic acid and oleic acid) on the efficacy of transdermal delivery of antigens by examining the skin specimens histologically (specific aim 1). To evaluate the effect of skin permeation enhancers on inducing immune responses in mice, permeation enhancers (retinoic acid and oleic acid) will be applied to the shaved skin prior to skin immunization with albumin or inactivated influenza virus as a model of soluble and particulate antigen respectively (specific aim 2). The immune responses to albumin and influenza virus antigen delivered through the skin will be determined by monitoring the following parameters: Albumin and influenza virus specific antibody titers in both serum and mucosal secretions, immunoglobulin isotype distribution, production of cytokines in spleen and draining lymph nodes. If use of a penetration enhancer can overcome the skin barrier and enhance the immune responses to inactivated viruses (particulate antigens) after TCI, this approach will be very innovative and open a way for advancing skin vaccination.